Cyclopentanophenanthrene compounds and process



United States Patent 3,193,554 CYQLGIENTANQPHENANTIRENE COM- POUNDS ANDPROCESS Alexander B. Gross, Fred A. Kincl, and Albert Bowers, MexicoCity, Mexico, assignors, by mesne assignments,

to Syntex Corporation, a corporation of Panama N0 Drawing. Filed Feb.21, I962, Ser. No. 174,682

Claims priority, application Mexico, Jan. 3, 1962, 65,582 19Clain1s.(Cl. 260-287) In the above fiormulastR and R represent hydrogen or ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; Rrepresents hydrogen or a lower alkyl group; and Z may be a double bondor a single bond between 05 and N-6. The acyl group is derived fromhydrocarbon carboxylic acids of less than 12 carbon atoms, which may besaturated or unsaturated, of straight, branched, cyclic or mixedaliphatic-cyclic chain, or aromatic, and may be substituted withfunctional groups such as hydroxyl, alkoxy of up to 5 carbon atoms,acyloxy of up to 12 carbon atoms, nit-r0, amino or halogen. Typical suchesters are the acetate, propiona-te, enant-hate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionateand fi-chloropropionateQ The compounds represented by the above formulasare hormones of the androgenic type which exhibit a separation betweentheir androgenic and anabolic activities, stimulate the action of thepituitary gland and show antiestrogenic and anti-progestationalactivity, and also inhibit luteinization.

The novel compounds object of the present invention are prepared by themethod illustrated as follows:

In the abve formulas R, R and R have the same meaning set forthpreviously. Ac represents the acyl group, preferably the acetyl group.

In effecting the process set forth above, the starting compound (I),which is a diacyla-te, preferably the diacet-ate, of A-andr-ostene-3B,l7fl-diol or of a :17u-lower alkyl derivative, istreated with ozone and the resulting compound is treated with hydrogenperoxide, thus giving rise to3,8,17,8-diacetoxy-5,6-seco-androstane-5-one-6-carboxylic acid (H), orthe 17 a-lower alkyl derivative. These compounds, upon treatment with achlorinating agent, preferably with thionyl chloride, produce therespective acid chlorides (III), which on further reaction with theazicle of an alkali metal, preferably with sodium azi-de, afford theazides of the corresponding acids (IV). By treatment of the latercompounds with acid at steam bath temperature, followed by conventionalisolation of the product, there are obtained the respective -acetoxy-6-aza-A -androstadienes (VII: R =Ac), which on conventionalsaponificati-on in alkaline medium produce the corresponding free NB-alcohols (VII: R zH).

By following a second sequence of reactions, the azides mentioned above(IV), are reacted with an amide, preferably with dimethylformamide, thusproducing the corresponding35,17fi-diacetoxy-5,7-seco-6-nor-androstan-7- isocyanates, which onhydrogenation in the presence of an adequate catalyst, such as platinumoxide, produce the respective 3,6,17B-diacetoxy-6-aza-androstanes (V).These compounds on reaction with hypoch-lorous acid followed bytreatment of the resulting N-chloro compounds with a base, such as forexample methanolic sodium hydroxide, at the reflux temperature, affordthe cor-responding 6-aza-A -androstane-3B,17fi-diols (VI: R=R =H).

The compounds obtained as set forth above, having a secondary hydroxylgroup in the molecule, for example in the 035 position (VI: R=H) or atthe G175 position (VII: R zR =H) when the C-17oz position is occupied byhydrogen, are acylated conventionally by reaction in pyridine with anacylating agent, such as the anhydride of a hydrocarbon carboxylic acidof the type set forth previously, to produce the corresponding 35 or1713- acylates (VI: Rzacyl; VII: R =acyl, R =H).

The compounds having a tertiary hydroxyl group in the molecule (VI, VII:R :I-I, R =alkyl) are conventionally esterified in the presence of'p-toluenesulfonic acid with an acylating agent such as for example ananhydride of the type set forth above, to produce in this manner therespective 17 8-acylates (VI, VII: R zacyl, R =alkyl).

The processes described above may be applied to the correspondingZa-met-hyl derivatives of the starting com- 3 pounds, thus forming theintermediate derivatives and the final products having a methyl group atthe 2a position.

The following specific examples serve to illustrate but are not intendedto limit the scope of the invention.

Example I A solution of 5.2 g. of the diacetate of A -androstene-3B,17[3-diol in 50 cc. of glacial acetic acid and 50 cc. of ethylacetate was placed in an ozonization tube and cooled in' an ice-saltbath. A stream of ozone was introduced for 2 hours (0.024 mol per hour),then 20 cc. of water and 3 cc. of 30% hydrogen peroxide were added andthe mixture was stirred vigorously. The mixture was heated for half anhour on the steam bath and then kept at room temperature for 48 hours.The resulting solution was concentrated to a small volume under vacuumand at the steam bath temperature, diluted with 20 cc. of methanol andpoured into water. The 'mixture was extracted with ether and the extractwas washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the residue from ether-pentaneafforded 3/3,17,3-diacetoxy-S,6-seco-androstan-5-one-6-carboxylic acid.

Example II A mixture of 5 g. of the above acid, 50 cc. of absoluteether, 5 cc. of dimethylformamide and 2.5 cc. of thionyl' chloride waskept for 1 hour at room temperature and then poured into ice-Water. Theether layer was separated, dried over anhydrous sodium sulfate andevaporated to dryness, thus yielding the chloride of SBJZB-diacetoxy-5,6-seco-androstan-5-one-6-carboxylic acid.

7 Example 111' v To 4 g. of the above chloride in 80 cc. of acetone wasadded 1.2 g. of sodium azide in 12 cc. of water and themixture was keptstanding for minutes and then poured into water and extracted withether. The ether extract was washed with Water, dried over sodiumsulfate and evaporated to dryness, thus giving the azide of36,17ediacetoxy-5,6-seco-androstan-5-one-6 carboxylic acid.

7 Example IV Example V A mixture of 4 g. of the azide obtained inaccordance with Example 111 and 10 cc. of dimethylformamidewas heated onthe steam bath until the evolution of nitrogen ceased (approximately 5minutes) 2 cc. of water was added and the mixture was cooled, thusproducing a crystalline precipitate of 38,17B-diacetoxy-5,7-seco-6-norandrostan-7-isocyanate.

Example Vl A solution of 2 g. of the above compound in 100 cc. of aceticacid was stirred with 200 mg. of platinum oxide under an atmosphere ofhydrogen until the uptake of 1 molar equivalent of hydrogen. Thecatalyst was removed by filtration. and the filtrate was evaporated todryness under reduced pressure. Crystallization of the residue fromacetonitrile afforded 35,17/8-diacetoxy-6-aza-androstane. L

' Example VII To 2 g. of the above compoundin 50 cc. of absolute etherwas added 5 cc. of a 1 M ether solution of hypochlorous acid. Theresulting mixture was kept standing for 5 minutesand then treated with 5cc. of a cold 0.5 N solution of sulfuric acid. The mixture was washedwith 0.5 N sodium hydroxide solution and the ether layer was separated,dried and evaporated to dryness, thus leaving as a residue theN-chloro-derivative of the starting compound. This derivative was boiledunder reflux with 40 cc. of 5% methanolic. sodium hydroxide solution for1 hour, then cooled and diluted with water. The precipitate formed wascolleced, dried and recrystallized from acetone, thus affording 6-aza-A-androstene-3p,17fl-diol.

Example VIII Androstenolone was treated with ethyl magnesium bromide togive 17a-ethyl-A -androsten-3,8,17f3-diol, which was conventionallyacetaylated with acetic anhydride in the presence of p-toluenesulfonicacid, to form the corresponding diacetate, which was then treated inaccordance with Examples 1, II, III, IV, V, VI and VII, thus producing.successively: 35,17fl-diacetoxy-l7a-ethyl 5,6secoandrostan-5-one-6-carboxylic acid, the chloride of3fl,17fidiacetoxy-17a-ethyl-5,G-seco-androstan-S-one-S-carboxylic acid,the azide of35,17B-diacetoxy-17a-ethyl-5,6-secoandrostan-5-0ne-6-carboxylic acid,17/3-acetoxy-17a-ethyl- 6-aza-A -androstadiene,3,8,17,6-diacetoxy-17a-ethyl-5,7- seco-6-nor-androstan-7-isocyanate,313,17B-diacetoxy 17athyl-G-aza-androstane and 17a-ethyl-6-aza-A-androstene- 3,8,17/i-diol.

. 7 Example X A solution of 0.l7 g. of potassium hydroxide in 2 cc. ofwater and 2.5 cc. of methanol was added over a period of 30 minutes to aboiling solution of 1 g. of 17fl-acetoxy- 6-aza-A -androstadiene in 30cc. of methanol, under an atmosphere of nitrogen. The boiling wascontinued for 2 hours further and then the solution was cooled,neutralized with acetic acid and concentrated under reduced pressure.

, By dilution with water, followed by crystallization of the precipitatefrom acetone-hexane, there was obtained 6-aza-A -androstadien-17/3-01.

By following the same proces, the compounds listed under I weretreated'to produce the products under II.

I II

17a-methyl-6-aza-A -androstadieuandrostadiene. 1 01 A mixtureof 1 g.of'6-aza-A3 androstadien-17 3-01, 4

(cc. of pyridine and 2 cc. of propionic anhydride was kept overnight atroom temperature, then poured into ice water and the precipitate formedwas collected, washed with water and dried. .By crystallization fromacetone- I II The dipropionate of 6-aza-A -androstene-3B,l7fi-diol. The3-pr0pi0nate of 17a-methyl-6- Example XII A solution of 5 g. ofl7a-methyl-6-aza-A -androstadien-l7/3-ol in 100 cc. of anhydrous benzenewas treated with -1 g. of p-toluenesulfonic acid and cc. of caproicanhydride and the mixture was kept at room temperature for 24 hours andthen poured into ice water; the resulting mixture was stirred in orderto hydrolyze the excess of anhydride. The benzene layer was separated,washed with 10% sodium carbonate solution and water, dried andevaporated. Crystallization of the residue from etherhexane afforded the17-caproate of 17amethyl-6-aza- A -androstadien175-01.

In the same manner there were treated 17a-ethy1-6- aza-A-androstadien-17,8-01, l7a-methyl-6-aza-A -androstene-3B,17B-diol3-propionate and 17a-ethyl-6-aza-A -androstene-3fi,175-dio13-propionate, to produce respectively: 17a-ethyl-6-aza-A-androstadien-17B-ol 17-caproate, 17a-methyl-6-aza-A-androstene-3/3,17fi-diol 3-propionate- 17-caproate and17a-ethyl-6-aza-M-androstene-3fi,17 3-diol 3-propionate-l7-caproate.

We claim:

1. A compound of the following formula:

wherein R and R are each selected from the group consisting of hydrogenand hydrocarbon carboxylic acyl of less than 12 carbon atoms; R isselected from the group consisting of hydrogen and lower alkyl and Z isselected from the group of a double bond and a saturated linkage betweenC-5 and N-6.

2. 6-aza-A -androstene-3B,17p-diol.

4. 17a-ethyl-6-aza-A -androstene-36,175-diol.

5. The dipropionate of 6-aza-A -androstene-3B,175- diol.

6. The dipropionate of 17a-methyl-6-aza-A -androstene- 313,17/8-diol.

7. The dipropionate of 17a-ethyl-6-aza-A -androstene- 35,17fl-diol.

8. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of6-aza-A -androstene-3B,17,8-diol.

9. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of17a-methyl-6-aza-A -androstene-3p, 17,8-diol.

19. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of17a-ethyl-6-azaA -androstene-3{3,175- diol.

11. The compound of the following formula:

wherein R is selected from the group consisting of hydrogen andhydrocarbon carboxylic acyl of less than 12 carbon atoms; and R isselected from the group consisting of hydrogen and lower alkyl.

12. 6-aza-A -androstadien--01.

13. 17a-methyl-6-aza-A -androstadien-1713-01.

14. 17methyl-6-aza-A -androstadien-17B-ol.

15. 6-aza-A -androstadien-17fi-ol-propionate.

16. 17a-methyl- 6 aza-A -androstadien-17B-ol-caproate.

17. 17 a-ethyl-6-aza-A -androstadien- 17fi-ol-caproate.

18. A process for preparing 6-aza-A -androstadien 175-01, whichcomprises treating the diacetate of A androstene-3B,l7fi-diol withozone, followed by hydrogen peroxide, reacting the resulting3/3,17/3-diacetoXy-5,6- seco-androstan-5-one-6-carboxylic acid withthionyl chloride, treating the acid chloride thus obtained with sodiumazide, reacting the resulting azide of 35,17,8-diacetoxy-5,6-seco-androstan-5-one-6-carboxylic acid with acetic acid at thetemperature of the steam bath to produce 17fl-acetoxy-6-aza-Aandrostadiene and conventionally saponifying this compound to produce6-aza-A -androstadien-l7fl-ol.

19. A process for preparing 17oc-l0W61' alkyl-6-aza- A-androstadien-175-01, which comprises treating the diacetate of 17a-lower alkyl-A -androstene-3fl,l7 3-diol with ozone, followed byhydrogen peroxide, reacting the resulting 17OL-lOW61'alkyd-3B,l7,8-diacetoxy-5,6-seco-androstan-5-one-6-carboxylic acid withthionyl chloride, treating the acid chloride thus obtained with sodiumazide, reacting the resulting azide of 17a-lower alkyl-3/3,l7,B-diacetoxy-S,6-seco-androstan-5-one-6-carboxy1ic acid with acetic acid atthe temperature of the steam bath to produce 17a-loweralkyl-l7,8-acetoxy-6-aza-A -androstadi ene and conventionallysaponifying this compound to produce l7a-lower alkyl-6-aza-A-androstadien-17,8-01.

References Cited by the Examiner UNITED STATES PATENTS 3 ,O22,312 2/ 62Wildi 2603 89 3,023,227 2/62 Atwater 260345 .3

FOREIGN PATENTS 1,118,197 11/61 Germany.

OTHER REFERENCES Ioska et al.: Chem. Abs, vol. 53, cols. 5341-2 (1959).Lettre et al.: Ber. dent. Chem., vol. 93, pp. 2860-4 (1960).

NICHOLAS S. RIZZO, Primary Examiner.

DUVAL T. MCCUTCHEN, WALTER A. MODANCE,

Examiners.

1. A COMPOUND OF THE FOLLOWING FORMULA: